Under conditions of normal oxygen tension (normoxia), translation of messenger RNAs (mRNAs) into proteins depends on the binding of eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m7-GpppG) 5′ cap of the mRNA. When oxygen tension is low (hypoxia), mammalian target of rapamycin (mTOR)–dependent signaling results in the sequestration of eIF4E, thus inhibiting cap-dependent translation. Uniacke et al. studied expression of the gene encoding the epidermal growth factor receptor (EGFR) and found that EGFR mRNA was translated under hypoxic conditions through a process that was dependent on hypoxia-inducible factor 2α (HIF-2α) but was not affected by the addition of transcription inhibitors to block the expression of HIF-2α target genes. EGFR mRNA was associated with polysomes in hypoxic cells, and knockdown of HIF-2α blocked its translation. HIF-2α was physically associated with polysomes containing EGFR mRNA, and RNA immunoprecipitation assays showed that the HIF-2α was associated with a region in the 3′-untranslated region (UTR) of EGFR mRNA. This association was indirect and depended on RNA-binding motif protein 4 (RBM4), which interacted with the N-terminal region of HIF-2α during hypoxia to recruit HIF-2α to EGFR mRNA. The RBM4–HIF-2α complex was captured by m7-GpppG–conjugated beads, and immunoprecipitation studies showed that the RBM4–HIF-2α complex bound to eIF4E2, a homolog of eIF4E. Silencing of eIF4E2, but not eIF4E, blocked the translation of EGFR mRNA, among others, during hypoxia. Under normoxic conditions, eIF4E was associated with polysomes, whereas under hypoxic conditions, eIF4E was replaced with eIF4E2. Inhibition of mTOR with rapamycin blocked mRNA translation under normoxic, but not hypoxic, conditions. Together, these data suggest that a reduction in oxygen tension causes a switch from eIF4E- to eIF4E2-dependent translation through a process that depends on HIF-2α.